By 2030, the global prevalence of Alzheimer's disease (AD) is predicted to reach 65.7 million. Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is important to identify preventive strategies that can reduce the risk of or delay the onset of AD [1]. Physical activity (PA) has potential as a preventative strategy. Our research [2, 3] and that of others [4, 5] shows that older adults who participate in PA experience larger gains in cognitive performance than do controls. Prospective studies also show that PA is associated with a lower risk of AD [6-9] and that the relationship between baseline PA and subsequent cognitive performance is moderated by a susceptibility gene for AD (apolipoprotein, APOE) [10-13]. However, the potential moderating role of APOE genotype on the effects of PA on cognitive performance has not been tested experimentally in humans; thus we do not know who receives the greatest cognitive benefits from PA. Additionally, we do not understand the mechanisms which explain how PA benefits cognitive performance. These gaps in the literature are the motivation behind our long range plan of research designed to further our understanding of the potential role of PA in the mitigation of cognitive decline and in the delay of AD. These gaps are also the impetus for this specific study in which we: 1) establish the feasibility of an 8-month PA intervention with persons with a family history of AD and use statistical modeling to inform the design of a future randomized control trial (RCT); 2) assess change in cognitive performance across the PA intervention and determine whether this change differs as a function of APOE genotype; 3) determine whether change in peripheral brain-derived neurotrophic factor, pBDNF (which is a plausible mechanism of the effects and has been linked to AD) predicts change in cognitive performance across the PA intervention; and 4) examine the differential effects of APOE genotype on the effects of PA on various cognitive domains. We will ascertain APOE genotype in 100 older cognitively normal individuals to identify APOE e4 carriers (n=30) and gender-matched non-carriers (n=30) to participate in an 8-month PA program. We will assess cognitive performance at baseline and will assess cognitive performance and pBDNF at the pre-test, mid-test, and post-test. This initial study will provide foundational evidence and will guide the development of a RCT further testing the moderating role of APOE genotype and the mediating role of pBDNF on the effects of PA on cognitive performance. The identification of effective interventions for the maintenance of cognitive performance in older adults at risk for AD has important public health implications because few preventive strategies for AD have been identified and because a therapy that delays the development of AD by 5 years could reduce the risk of AD by 50%. PA has promise in this regard and is particularly attractive because it is cost-effective and has relatively few negative side-effects. Further, if PA is beneficial for persons with a genetic risk for AD, this cold be particularly important because these individuals show signs of preclinical AD in middle-age [14, 15]. PUBLIC HEALTH RELEVANCE: Delaying the onset of AD by 6 months can reduce the prevalence of AD by 100,000 persons after 10 years [16]; thus, understanding the potential of PA as a preventative treatment to delay AD has important public health implications. If our research indicates that PA is specifically beneficial for persons with a genetic risk for AD, this would be particularly important because evidence suggests that these individuals show signs of preclinical AD in middle-age [14, 15]. Further, if our research demonstrates that peripheral BDNF is an underlying mechanism of the effect, this would contribute to our ability to effectively prescribe the optimal dose of PA for cognitive benefits. This line of research may ultimately establish PA as a behavioral preventive treatment for individuals with an APOE genotype that puts them at increased genetic risk for AD.